We have previously shown that endothelium-dependent vascular relaxation to acetylcholine is abnormal in hypertensive patients. However, because previous investigations have invariably used acetylcholine to test endothelial function, it is not known whether the impaired endothelium- dependent vascular responses of hypertensive patients are due to an abnormality isolated to the muscarinic receptor. To address this issue, we studied the vasodilator responses to the endothelium-dependent muscarinic agent acetylcholine, and the endothelium-dependent non- muscarinic agent substance P. We also studied the response to sodium nitroprusside, an endothelium-independent agent. The study included 8 hypertensive patients ( 6 male; age 50+/-12 years) and 8 normal controls (4 male; age 49+/-9 years). Drugs were infused into the brachial artery and the forearm blood flow response was measured by strain gauge plethysmography. As shown before, the response to acetylcholine was significantly reduced in hypertensive patients compared to normal controls; however, no difference was observed in the response to sodium nitroprusside. Substance P produced a vasodilator response in both groups; however, this response was significantly reduced in the hypertensive patients compared to controls. A significant correlation was found between the vascular responses to substance P and acetylcholine, while no correlation was observed between the response to sodium nitroprusside and either of the endothelium-dependent vasodilators. Thus, hypertensive patients have abnormal endothelium- dependent responses not only to acetylcholine but also to substance P. These findings indicate that the impaired endothelial function of hypertensive patients is not related to a defect specific for muscarinic receptors, and suggest a broader abnormality of the endothelium.